Cystine (—S—S—) bridges are common structural motifs in naturally occurring cyclic peptides. In some cases, these disulfide bridges act as reactive functional groups. In many other cases however, the cystine bridge serves only a skeletal, structural role, maintaining secondary and tertiary structure. Disulfide bonds in peptides and other compounds are highly reactive under broad-ranging conditions, and therefore useful peptides containing disulfide bonds which have a structural role are at risk of denaturation, resulting in loss of properties. There is accordingly some interest in developing methods for creating more robust bridges in such compounds—such as dicarba (—C—C—) containing bridges, which are not as reactive, so as to produce compounds having the activity of, or similar activity to, the disulfide-containing polypeptides, but with better biostability.
Once a suitably strategy for forming such dicarba bridges is established, it is of additional interest to be able to form multiple dicarba bridges—selectively. By way of explanation, a peptide possessing four cysteine residues, and two cystine bridges, has three topoisomers—the [1,3],[2,4]-isomer (globule), the [1,4],[2,3]-isomer (ribbon) and the [1,2],[3,4]-isomer (bead). It would be useful to be able to selectively form one of these isomers, without any of the other two topoisomers. It is also of interest to be able to form one or more dicarba bridges using chemistry that does not destroy any disulfide bridges that are present, so that dicarba-disulfide containing compounds can additionally be formed. It is of further interest to have a dicarba bridge forming method that can take place despite the presence of disulfide, which could otherwise interfere with dicarba bridge-forming reactions.
Once this is achievable, it is of interest to be able to form dicarba-containing analogues of a range of disulfide-containing peptides, such as conotoxins. It is also of interest to form peptide and non-peptide compounds containing one or more intramolecular dicarba bridge, and an olefin-handle enabling reaction to other moieties.